Project Summary Autism spectrum disorders (ASD) comprise a group of complex neurodevelopmental disorders that affect 1 in 68 children in the United States. ASD is phenotypically and etiologically heterogeneous, making it challenging to uncover the underlying genetic / cellular pathophysiology and to efficiently design drugs with widespread clinical benefits. Induced pluripotent stem cells (iPSCs) constitute an ideal model for understanding complex diseases with strong genetic component such as ASD. Although iPSCs have been generated for monogenetic ASD diseases, the demonstration of disease-specific pathogenesis in complex and heterogeneous diseases such as idiopathic ASD is a current challenge in the field. Insulin-Like Growth Factor 1 (IGF1) has recently emerged as a potentially efficient treatment option for both syndromic and non-syndromic forms of ASD. A growing body of evidence accumulated in the past years in both rodent and human ASD models have established IGF1 as one of the most promising ASD therapeutic interventions to date. While IGF1 effects downstream of ligand binding (IGF1 receptor) have been comprehensively studied in the literature, how IGF1 activity may lead to therapeutic recover in the ASD context is still largely unknown. This proposal will focus on understanding the molecular mechanisms underlying IGF1-therapeutic activity in iPSC-derived neural cells from ASD individuals. This will be achieved by performing transcriptional profiling on iPSC-derived neural cells from a previously characterized cohort of ASD patients that show functional response to IGF1 treatment in vitro. The neural cultures will be treated during neuronal maturation or at the mature stage with IGF1 and their molecular responses to IGF1 after treatment will be evaluated and compared to the responses on neurotypical controls. This proposal will generate a comprehensive list of differentially regulated genes and molecular interactions that will potentially produce valuable information about specific downstream targets of IGF1 in the context of ASD patients' neural cells. Additionally, the transcriptional profile dataset and analysis generated in this proposal will provide a unique resource for other researchers interested in IGF1 downstream interactions in ASD and will potentially help finding candidate pathways and targets for effective ASD clinical intervention.